Description:

The goal of the CHARM Preserved trial was to evaluate the effects of the long-acting angiotensin II type 1 receptor blocker candesartan compared with placebo in patients with symptomatic heart failure (HF) and an ejection fraction (EF) >40%.

Hypothesis:

Treatment with the angiotensin II receptor antagonist candesartan with or without an angiotensin-converting enzyme (ACE) inhibitor will be associated with a reduction in the primary endpoint of cardiovascular (CV) death or HF hospitalizations in patients with symptomatic HF and an EF >40%.

Patient Populations:

Age >18 years with symptomatic CHF corresponding to New York Heart Association (NYHA) class II-IV on patients with LVEF >40%, and history of hospitalization for a cardiac reason

Exclusions:

Serum creatinine ≥3 mg/dl; current serum potassium ≥5.5 mEQ/l, history of marked ACE inhibitor-induced hyperkalemia (serum K+ .5.9 mEQ/l), or life-threatening adverse event; known bilateral renal artery stenosis; current symptomatic hypotension; persistent systolic or diastolic hypertension; stroke, acute MI, or open heart surgery within the last four weeks; previous or planned heart transplant within the next six months; or life expectancy <2 years

Drug/Procedures Used:

CHARM consists of three independent, parallel, placebo-controlled studies in patients with symptomatic HF. In the CHARM Preserved component trial, patients with left ventricular ejection fraction (LVEF) >40% (n=3,025) were randomized to candesartan (4 or 8 mg/day, titrated to target dose of 32 mg; n=1,514) or placebo (n=1,509) and followed for a minimum of two years.

Concomitant Medications:

ACE inhibitors 19%, beta-blockers 56%, and diuretics 75%

Principal Findings:

Mean baseline EF was 54%. ACE inhibitor use was reported in only 19% of patients, with beta-blocker use in 56% and diuretics in 75%. The primary endpoint of CV death or HF hospitalizations occurred in 22.0% of patients in the candesartan arm and 24.3% in the placebo arm (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.77-1.03, p=0.118). After adjustment for baseline covariates, the adjusted HR was 0.86 (p=0.051). Among the components of the primary endpoint, there was no difference in CV death (HR 0.99, p=0.918), but HF hospitalizations trended lower (HR 0.85, p=0.072; adjusted p=0.047).

The percent of patients with investigator reported HF hospitalizations and the total number of hospitalizations were both lower in the candesartan arm (p=0.017 and p=0.014, respectively). New onset diabetes occurred less frequently in the candesartan arm (4% vs. 7%, HR 0.60, 95% CI 0.41-0.86, p=0.005). Patients discontinued study drug more often in the candesartan arm (17.8% vs. 13.5%, p=0.001), with the reason for discontinuation more often hypotension and increased creatinine than in the placebo arm.

Interpretation:

Among patients with symptomatic HF and an EF >40%, treatment with candesartan was associated with a nonsignificant reduction in the primary endpoint of CV death or HF hospitalizations. Few therapeutic options have been specifically studied in patients with symptomatic HF and preserved EF, a generally lower risk population among HF patients.

The present trial is the largest trial specifically in this population. The lower risk is evident when evaluating the event rates for CV death or HF hospitalizations in the CHARM Preserved trial (22.0% with candesartan and 24.3% with placebo) and the rate in the CHARM Added trial (37.9% with candesartan and 42.3% with placebo). Patients treated with candesartan should be carefully monitored, given the increase in study drug discontinuation due to hypotension and increased creatinine.

References:

Presented by S. Yusuf at the European Society of Cardiology Congress, Vienna, Austria, September 2003.